4505 Background: Thromboembolic events (TEs) occur at an increased rate in patients with advanced malignancies including androgen-independent prostate cancer (AIPC). DN-101, a new high-dose oral formulation of calcitriol (1,25-dihydroxycholecalciferol), is the active form of Vitamin D and the natural ligand for the nuclear receptor VDR. Calcitriol upregulates thrombomodulin, a natural anticoagulant, and downregulates tissue factor, a procoagulant both in vitro and in vivo. Further, VDR knockout mice demonstrate increased susceptibility to thrombosis. ASCENT is a double-blind, placebo-controlled study in 250 men with metastatic AIPC. Efficacy results have been previously reported (ASCO, 2005). Methods: 250 patients were randomized 1:1 to docetaxel 36 mg/m2 plus 45 μg DN-101 weekly or to the same docetaxel regimen plus placebo. In this exploratory analysis the incidence of TE (defined as deep venous thrombosis (DVT), pulmonary embolism (PE), myocardial infarction (MI), cerebrovascular accident (CVA) and arterial thrombosis (AT)) in the two study groups was compared using the Fisher’s exact test. Results: There were fewer patients with serious adverse events (SAEs) in the DN-101 group than in the placebo group (27 % vs. 41%). As shown in the table , DN-101 treated patients experienced fewer TEs including fewer TE SAEs, Grade 3 or 4 TEs and all grade TEs. No imbalance in baseline use of anticoagulants was observed. Conclusions: The well-described effects of calcitriol on protein components of the coagulation cascade provide a biologic basis for the observed reduction in thromboembolic events in the DN-101 treated patients. This hypothesis should be tested prospectively in future studies of DN-101. [Table: see text] [Table: see text]
Safety and efficacy of high dose pulse calcitriol and docetaxel for androgen-independent prostate cancer
